Accurate free-energy calculations provide mechanistic insights into molecular recognition and conformational equilibrium of chemical drugs and proteins, and thus can be valuable in drug discovery. We applied an end-point free energy calculation method, termed VM2, to estimating the binding free energies of ligand-protein systems. VM2 uses empirical force fields and implicit solvent models, treats the protein binding site as fully flexible, and estimates free energies as sums over local energy wells. The calculations are found to yield very good agreement with experimental results for p38α MAP kinase inhibitors. The calculations revealed multiple stable, complex conformations and changes in protein and inhibitor conformations, as well as balance in several energetic terms and configurational entropy loss. Our results provide the driving forces of binding and also suggest the dynamic equilibrium between the DFG-in and DFG-out states. These results provide relevant physics that can aid in designing inhibitors and understanding protein conformational equilibrium. We further applied the method to inhibitors binding CDK8 for further inhibitor design.

Modeling molecular recognition: Free energy calculations for inhibitors binding to protein kinases

254th National Meeting (2017)

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